Amparo Galán

Combined use of high‐sensitivity ST2 and NTproBNP to improve the prediction of death in heart failure

To address the incremental usefulness of biomarkers from different disease pathways for predicting risk of death in heart failure (HF).

The Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) study: Prevalence and risk factors

BACKGROUND AND PURPOSE The ongoing population-based Barcelona-Asymptomatic Intracranial Atherosclerosis (Barcelona-AsIA) study is a prospective study that plans to investigate the natural history of asymptomatic intracranial atherosclerosis (AsIA) in a Caucasian-Mediterranean population, which remains unknown until now. The present study aims to determine the prevalence of AsIA and associated risk factors in the final study cohort. METHODS Crossover, population-based study of a representative sample (randomly selected from our reference population) older than 50 with a moderate-high vascular risk assessed by the vascular equation REGICOR and prior history of neither stroke nor ischemic heart disease. Anthropometric, demographic, clinical data and blood samples were collected at baseline. All individuals underwent a complete extracranial and transcranial color-coded duplex (TCCD) examination. TCCD criteria were used to identify and classify the degree of intracranial stenoses. RESULTS A total of 933 subjects (64% men, mean age 66.3 years) were included in the study. One or more intracranial stenoses were detected at baseline in 80 subjects (8.6%) of whom 31 (3.3%) had moderate-severe lesions. The higher the REGICOR scores the greater the prevalence of AsIA (6.6%, 10.2% and 25% for REGICOR scores 5-9, 10-14 and ≥15, p<0.001). Diabetes (OR 2.95; 95% CI (1.68-5.18); p<0.001), age (OR 1.05; 95% CI (1.02-1.08); p=0.001) and hypertension (OR 1.78; 95% CI (1.02-3.13); p=0.04) were independently associated with any degree of AsIA, while diabetes (OR 2.85; 95% CI (1.16-6.96); p=0.02) and age kept independently associated with moderate-severe AsIA. CONCLUSION The prevalence of AsIA and moderate-severe AsIA in stroke-free Caucasians with a moderate-high vascular risk were 8.6% and 3.3% respectively. Diabetes and age were independently associated with moderate-severe AsIA.

Biological Signatures of Asymptomatic Extra- and Intracranial Atherosclerosis The Barcelona-AsIA (Asymptomatic Intracranial Atherosclerosis) Study

Background and Purpose— Intracranial atherosclerotic disease (ICAD) remains a challenge for stroke primary and secondary prevention. Molecular pathways involved in the development of ICAD from its asymptomatic stages are largely unknown. In our population-based study, we aimed to compare the risk factor and biomarker profiles associated with intracranial and extracranial asymptomatic cerebral atherosclerosis. Methods— The Asymptomatic Intracranial Atherosclerosis (AsIA) study cohort includes a random sample population of 933 white subjects >50 years with a moderate to high vascular risk (based on REGICOR score) and without a history of stroke (64% males; mean age, 66 years). Carotid and intracranial atherosclerosis were screened by cervical and transcranial color-coded Duplex ultrasound, being moderate to severe stenoses confirmed by MR angiography. We registered clinical and anthropometric data and created a biobank with blood samples at baseline. A panel of biomarkers involved in atherothrombogenesis was determined: C-reactive protein, asymmetric-dimethylarginine, resistin, and plasminogen activator inhibitor-1. Insulin resistance was quantified by Homeostasis Model Assessment index. Results— After multinomial regression analyses, male sex, hypertension, smoking, and alcoholic habits were independent risk factors of isolated extracranial atherosclerotic disease. Diabetes and metabolic syndrome conferred a higher risk for ICAD than for extracranial atherosclerotic disease. Moreover, metabolic syndrome and insulin resistance were independent risk factors of moderate to severe ICAD but were not risk factors of moderate to severe extracranial atherosclerotic disease. Regarding biomarkers, asymmetric-dimethylarginine was independently associated with isolated ICAD and resistin with combined ICAD–extracranial atherosclerotic disease. Conclusions— Our findings show distinct clinical and biological profiles in subclinical ICAD and extracranial atherosclerotic disease. Insulin resistance emerged as an important molecular pathway involved in the development of ICAD from its asymptomatic stage.

Structural brain changes and cognition in relation to markers of vascular dysfunction

The aim was to investigate the relationship between blood markers of vascular dysfunction with brain microstructural changes and cognition. Eighty-six participants from the Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) neuropsychology study were included. Subjects were 50-65 years old, free from dementia and without history of vascular disease. We assessed correlations of blood levels of inflammatory biomarkers (C-reactive protein [CRP] and resistin) and fibrinolysis inhibitors (plasminogen activator inhibitor-1 [PAI-1] and A-lipoprotein (Lp (a)) with fractional anisotropy (FA) measurements of diffusion tensor images (DTI), regional gray matter (GM) volumes and performance in several cognitive domains. Increasing levels of C-reactive protein and PAI-1 levels were associated with white matter (WM) integrity loss in corticosubcortical pathways and association fibers of frontal and temporal lobes, independently of age, sex and vascular risk factors. PAI-1 was also related to lower speed and visuomotor/coordination. None of the biomarkers were related to gray matter volume changes. Our findings suggest that inflammation and dysregulation of the fibrynolitic system may be involved in the pathological mechanisms underlying the WM damage seen in cerebrovascular disease and subsequent cognitive impairment.

Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score

BACKGROUND Limited data exists regarding biomarker use to predict left ventricular (LV) reverse remodeling (R2). Our aim was to examine the value of soluble ST2 (ST2), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and galectin-3 relative to LV-R2 in systolic heart failure (HF), and to develop a clinical score for LV-R2 prediction. METHODS R2 was defined as a) LV ejection fraction (LVEF) increase ≥15%, or b) LVEF increase ≥10% plus reduction of LV end-systolic diameter index ≥20% or LV end-systolic volume ≥40%, for 12 months. RESULTS We studied 304 patients (79.6% men, mean age 66.1 ± 12.3 years) with baseline LVEF <40%. R2 was observed in 104 patients (34.2%). In univariable logistic regression, factors associated with R2 were age (p=0.02), non-ischemic etiology of HF (p<0.001), NYHA functional class (p=0.02), baseline LVEF (p=0.005), absence of left bundle branch block (LBBB; p=0.002), ST2 (p=0.004), NT-proBNP (p=0.005), and hs-cTnT (p<0.001); HF duration achieved borderline significance (p=0.08). In multivariable analysis, ST2 remained the only biomarker associated with LV-R2. We developed the ST2-R2 score for use in clinical practice for predicting R2; variables included were ST2 <48 ng/mL, non-ischemic etiology, absence of LBBB, HF duration <12 months, baseline LVEF <24%, and β-blocker treatment. The score had an area under the curve of 0.79 in the derivation cohort and 0.73 in a separate validation cohort. CONCLUSIONS The ST2-R2 score, which includes the novel biomarker ST2 and five clinical variables, reasonably predicts LV-R2 in systolic HF patients. ST2 was the only studied biomarker that was independently associated with R2.

The population-based Barcelona-Asymptomatic Intracranial Atherosclerosis Study (ASIA): rationale and design

BackgroundLarge-artery intracranial atherosclerosis may be the most frequent cause of ischemic stroke worldwide. Traditional approaches have attempted to target the disease when it is already symptomatic. However, early detection of intracranial atherosclerosis may allow therapeutic intervention while the disease is still asymptomatic. The prevalence and natural history of asymptomatic intracranial atherosclerosis in Caucasians remain unclear. The aims of the Barcelona-ASymptomatic Intracranial Atherosclerosis (ASIA) study are (1) to determine the prevalence of ASIA in a moderate-high vascular risk population, (2) to study its prognostic impact on the risk of suffering future major ischemic events, and (3) to identify predictors of the development, progression and clinical expression of this condition.Methods/DesignCross-over and cohort, population-based study. A randomly selected representative sample of 1,503 subjects with a mild-moderate-high vascular risk (as defined by a REGICOR score ≥ 5%) and with neither a history of cerebrovascular nor ischemic heart disease will be studied. At baseline, all individuals will undergo extracranial and transcranial Color-Coded Duplex (TCCD) ultrasound examinations to detect presence and severity of extra and intracranial atherosclerosis. Intracranial stenoses will be assessed by magnetic resonance angiography (MRA). Clinical and demographic variables will be recorded and blood samples will be drawn to investigate clinical, biological and genetic factors associated with the presence of ASIA. A long-term clinical and sonographic follow-up will be conducted thereafter to identify predictors of disease progression and of incident vascular events.DiscussionThe Barcelona-ASIA is a population-based study aiming to evaluate the prevalence and clinical importance of asymptomatic intracranial large-artery atherosclerosis in Caucasians. The ASIA project may provide a unique scientific resource to better understand the dynamics of intracranial atherosclerosis from its early stages and to identify new potential therapeutic targets for this condition.

Cognitive Patterns in Relation to Biomarkers of Cerebrovascular Disease and Vascular Risk Factors

Background: Risk factors for vascular cognitive impairment (VCI) are the same as traditional risk factors for cerebrovascular disease (CVD). Early identification of subjects at higher risk of VCI is important for the development of effective preventive strategies. In addition to traditional vascular risk factors (VRF), circulating biomarkers have emerged as potential tools for early diagnoses, as they could provide in vivo measures of the underlying pathophysiology. While VRF have been consistently linked to a VCI profile (i.e., deficits in executive functions and processing speed), the cognitive correlates of CVD biomarkers remain unclear. In this population-based study, the aim was to study and compare cognitive patterns in relation to VRF and circulating biomarkers of CVD. Methods: The Barcelona-AsIA Neuropsychology Study included 747 subjects older than 50, without a prior history of stroke or coronary disease and with a moderate to high vascular risk (mean age, 66 years; 34.1% women). Three cognitive domains were derived from factoral analysis: visuospatial skills/speed, verbal memory and verbal fluency. Multiple linear regression was used to assess relationships between cognitive performance (multiple domains) and a panel of circulating biomarkers, including indicators of inflammation, C-reactive protein (CRP) and resistin, endothelial dysfunction, asymmetric dimethylarginine (ADMA), thrombosis, plasminogen activator inhibitor 1 (PAI-1), as well as traditional VRF, metabolic syndrome and insulin resistance (homeostatic model assessment for insulin resistance index). Analyses were adjusted for age, gender, years of education and depressive symptoms. Results: Traditional VRF were related to lower performance in verbal fluency, insulin resistance accounted for lower performance in visuospatial skills/speed and the metabolic syndrome predicted lower performance in both cognitive domains. From the biomarkers of CVD, CRP was negatively related to verbal fluency performance and increasing ADMA levels were associated with lower performance in verbal memory. Resistin and PAI-1 did not relate to cognitive function performance. Conclusion: Vascular risk factors, and markers of inflammation and endothelial dysfunction predicted lower performance in several cognitive domains. Specifically, cognitive functions associated with CRP are typically affected in VCI and overlap those related to VRF. ADMA indicated a dissociation in the cognitive profile involving verbal memory. These findings suggest that inflammation and endothelial dysfunction might play a role in the predementia cognitive impairment stages.

Serum Myostatin Levels in Chronic Heart Failure

Muscle wasting is common in advanced heart failure. Myostatin is an important modulator of muscle catabolism. We measured serum levels of myostatin and its propeptide in patients with chronic heart failure and analyzed their relationships with clinical parameters and prognosis. The study included 70 patients: 30 in New York Heart Association (NYHA) functional class I-II and 40 in class III-IV. Their mean ejection fraction was 32%+/-12%. The mean follow-up time was 17.9+/-1.3 months. Thirteen patients (18.6%) died. No correlation was found between myostatin and myostatin propeptide levels. Nor was the myostatin or myostatin propeptide level correlated with age, sex, left ventricular ejection fraction, symptom duration, or the level of N-terminal probrain natriuretic peptide (NT-proBNP) or tumor necrosis factor-alpha receptor type-2 (TNFalpha R2). Moreover, no relationship was observed between the myostatin or myostatin propeptide level and NYHA functional class or mortality, in contrast to the relationships found with NT-proBNP (P< .001 and P< .001, respectively) and TNFalpha R2 (P=.001 and P=.005, respectively) levels. In conclusion, there was no relationship between the myostatin or myostatin propeptide level and any parameter of disease severity or prognosis in patients with chronic heart failure.

Niveles séricos de miostatina en insuficiencia cardiaca crónica

La afeccion muscular es frecuente en la insuficiencia cardiaca avanzada. La miostatina es un importante modulador del catabolismo muscular. Analizamos la concentracion serica de miostatina y su propeptido en pacientes con insuficiencia cardiaca cronica y su relacion con parametros clinicos y el pronostico. Se incluyo a 70 pacientes en clase funcional I-II (30) y III-IV (40) de la NYHA, con una media de fraccion de eyeccion del 32% ± 12%. El seguimiento medio fue 17,9 ± 1,3 meses. Fallecieron 13 pacientes (18,6%). No encontramos correlacion entre la concentracion de miostatina y la de su propeptido. Tampoco entre estos y edad, sexo, fraccion de eyeccion, duracion de los sintomas, concentraciones de NT-proBNP y de r2-TNFα. Ni miostatina ni su propeptido se relacionaron con la clase funcional ni con la mortalidad, a diferencia de NT-proBNP (p

Multimarker Strategy for Heart Failure Prognostication. Value of Neurohormonal Biomarkers: Neprilysin vs NT-proBNP

INTRODUCTION AND OBJECTIVES Neprilysin breaks down numerous vasoactive peptides. The soluble form of neprilysin, which was recently identified in heart failure, is associated with cardiovascular outcomes. Within a multibiomarker strategy, we directly compared soluble neprilysin and N-terminal pro-B-type natriuretic peptide as risk stratifiers in a real-life cohort of heart failure patients. METHODS Soluble neprilysin, N-terminal pro-B-type natriuretic peptide, ST2, and high-sensitivity troponin T levels were measured in 797 consecutive ambulatory heart failure patients followed up for 4.7 years. Comprehensive multivariable analyses and soluble neprilysin vs N-terminal pro-B-type natriuretic peptide head-to-head assessments of performance were performed. A primary composite endpoint included cardiovascular death or heart failure hospitalization. A secondary endpoint explored cardiovascular death alone. RESULTS Median soluble neprilysin and N-terminal pro-B-type natriuretic peptide concentrations were 0.64ng/mL and 1187 ng/L, respectively. Both biomarkers significantly correlated with age (P<.001) and ST2 (P<.001), but only N-terminal pro-B-type natriuretic peptide significantly correlated with estimated glomerular filtration rate (P<.001), body mass index (P<.001), left ventricular ejection fraction (P=.02) and high-sensitivity troponin T (P<.001). In multivariable Cox regression analyses, soluble neprilysin remained independently associated with the composite endpoint (hazard ratio=1.14; 95% confidence interval, 1.02-1.27; P=.03) and cardiovascular death (hazard ratio=1.15; 95% confidence interval, 1.01-1.31; P=.04), but N-terminal pro-B-type natriuretic peptide did not. The head-to-head soluble neprilysin vs N-terminal pro-B-type natriuretic peptide comparison showed good calibration and similar discrimination and reclassification for both neurohormonal biomarkers, but only soluble neprilysin improved overall goodness-of-fit. CONCLUSIONS When added to a multimarker strategy, soluble neprilysin remained an independent prognosticator, while N-terminal pro-B-type natriuretic peptide lost significance as a risk stratifier in ambulatory patients with heart failure. Both biomarkers performed similarly in head-to-head analyses.